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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rat neu oncogene product is a member of the epidermal growth factor (EGF) receptor subgroup of the superfamily of growth factor receptor tyrosine kinases. The oncogenic activation of the neu protein occurs by a point mutation within its transmembrane region which results in an increase in its tyrosine kinase activity. Using three different forms of neu expressed in insect cells via baculovirus infection, we have examined the biochemical differences between the normal and transforming forms of neu and investigated the role of the transmembrane domain in its tyrosine kinase activity. One form of neu which was expressed in insect cells consisted of the complete tyrosine kinase domain but lacked the extracellular and transmembrane regions (designated NTK). The other two forms consisted of the tyrosine kinase domain, the transmembrane domain, and 40 amino acids of the extracellular domain. One of these transmembrane forms of neu contained the normal valine residue at position 664 within the transmembrane region (MS-N), while the other contained the oncogenic glutamic acid residue at this position (MS-T). Direct comparisons of NTK, MS-N, and MS-T have shown that the NTK protein is capable of the highest extents of both autophosphorylation activity and the tyrosine phosphorylation of exogenous substrate, suggesting that the presence of the transmembrane region of neu suppresses the tyrosine kinase activity of this receptor. In addition, we have found that the oncogenic point mutation within the transmembrane region stimulates the tyrosine kinase activity of the neu protein by allowing it to more effectively utilize Mg2+. Overall, the results of these studies suggest that the valine to glutamic acid substitution at position 664 may at least partially relieve a negative constraint imparted by the membrane-spanning domain on the tyrosine kinase activity of neu and enables a more effective use of Mg2+ in the catalysis of tyrosine phosphorylation of exogenous substrates.
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PMID:Biochemical comparisons of the normal and oncogenic forms of insect cell-expressed neu tyrosine kinases. 135 72

The C-erbB-2 gene was first found in human genomic DNA as a sequence which had homology in nucleotide sequence to the V-erbB by molecular hybridization under relaxed conditions. The product of this gene is a receptor type protein-tyrosine kinase which has a structure highly related to that of epidermal growth factor receptor (EGF-r: C-erbB-1). The proto-neu gene is a rat counterpart of the C-erb B-2 gene. The C-erbB-2 gene is also called as the HER-2 gene. The C-erbB-2 gene acquires the ability to transform NIH 3 T 3 cells by, 1) mutation which alters valine 659 in transmembrane region to glutamic acid as was found in neu gene activation, 2) deletion of c-terminal regulatory domain or 3) gene-amplification or overexpression. C-erbB-2 expresses in human embryos on mucous membranes and glands, but only faintly in adult tissues. High expression or gene amplification in human tumor appeared to be an indication for high risk of metastasis or high degree of malignancy.
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PMID:[Proto-oncogene C-erbB-2 and human cancer]. 196 37

The Drosophila epidermal growth factor receptor homolog (DER) displays sequence similarity to both the epidermal growth factor (EGF) receptor and the neu vertebrate proteins. We have examined the possibility of deregulating the tyrosine kinase activity of DER by introducing structural changes which mimic the oncogenic alterations in the vertebrate counterparts. Substitution of valine by glutamic acid in the transmembrane domain, in a position analogous to the oncogenic mutation in the rat neu gene, elevated the in vivo kinase activity of DER in Drosophila Schneider cells sevenfold. A chimera containing the oncogenic neu extracellular and transmembrane domains and the DER kinase region, also showed a threefold elevated activity relative to a similar chimera with normal neu sequences. Double truncation of DER in the extracellular and cytoplasmic domains, mimicking the deletions in the v-erbB oncogene, did not however result in stimulation of in vivo kinase activity. The chimeric constructs were also expressed in monkey COS cells, and similar results were obtained. The ability to enhance the DER kinase activity by a specific structural modification of the transmembrane domain demonstrates the universality of this activation mechanism and strengthens the notion that this domain is intimately involved in signal transduction. These results also support the inclusion of DER within the tyrosine-kinase receptor family.
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PMID:Enhancement of tyrosine kinase activity of the Drosophila epidermal growth factor receptor homolog by alterations of the transmembrane domain. 197 62

We investigated the effect of an activated c-erbB-2 gene (also known as ERBB2) on metastatic potential. The c-erbB-2 gene was activated by mutation of the valine at position 659 within the transmembrane domain to glutamic acid. The activated c-erbB-2 expression vector was transfected into low-metastatic-potential NL-4 cells, which were established from a metastatic variant of murine colon adenocarcinoma 26. All 10 clones produced lung metastases in BALB/c mice injected via the tail vein. Eight of the 10 clones expressed messenger RNA (mRNA) of activated c-erbB-2 and showed morphological alteration; seven of the eight produced significantly enhanced experimental metastatic activity compared with that of untransfected NL-4 or NL-4neo cells, and one had metastatic ability similar to that of NL-4 cells. Two clones did not express c-erbB-2 mRNA and did not show morphological alteration or highly metastatic phenotype. Five of the 10 clones subcutaneously implanted in the flank failed to produce metastasis in the lungs or other organs of the mice. The metastatic ability of the other five clones was not determined. These results indicate that the activated c-erbB-2 gene can enhance experimental but not spontaneous metastatic potential in NL-4 cells, suggesting participation of the gene in the metastatic process after initial arrest and lodgement in the capillary bed.
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PMID:Low metastatic potential of clone from murine colon adenocarcinoma 26 increased by transfection of activated c-erbB-2 gene. 221 5

The mutant mouse waved-2 (wa-2) is strikingly similar to transforming growth factor alpha-deficient mice generated by gene targeting in embryonic stem cells. We confirm that wa-2 is a point mutation (T-->G resulting in a valine-->glycine substitution at residue 743) in the gene encoding the epidermal growth factor (EGF) receptor. wa-2 fibroblastic cells lack high-affinity binding sites for EGF, and the rate of internalization of EGF is retarded. Although the tyrosine kinase activity of wa-2 EGF receptors is significantly impaired, NIH 3T3 cells lacking endogenous EGF receptors but overexpressing recombinant wa-2 EGF receptor cDNA are mitogenically responsive to EGF. While young and adult wa-2 mice are healthy and fertile, 35% of wa-2 mice born of homozygous wa-2 mothers die of malnutrition because of impaired maternal lactation.
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PMID:A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation. 753 93

A single missense mutation in the human erbB-2 proto-oncogene (HER2N) efficiently transforms cultured NIH/3T3 fibroblasts. The transforming allele (HER2VE) contains a glutamic acid residue at position 659, instead of a valine, in the transmembrane region of the growth factor receptor. Receptor action is dependent on oligomerization. We have investigated the ability of erbB-2 gene variants with mutations in the intracellular tyrosine kinase domain to revert the transformed phenotype of cells. These variants most likely form hetero-oligomers with the transforming oncogene. Two receptor variants were constructed and introduced into cells expressing the oncogenic form of the human erbB-2 gene, HER2VE. The mutant HER2N delta contains a deletion of a large part of the kinase domain including the ATP binding site. This mutant had no effect on the growth of transformed cells, although it was found to interact with HER2VE. HER2N delta is phosphorylated in the presence, but not in the absence of HER2VE. A second mutant was constructed, HER2VEK753A, which contains both a mutation in the transmembrane region and a mutation in the ATP binding site of the kinase domain. This mutant led to a reversion of the transformed phenotype and significantly decreased growth in soft agar of HER2VE transformed cells. A concomitant increase in phosphorylated receptors was observed. These results indicate that an intact kinase domain is required for the oncogenic action of HER2VE and that transformation parameters can be suppressed by kinase domain mutants.
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PMID:NIH/3T3 cells transformed with the activated erbB-2 oncogene can be phenotypically reverted by a kinase deficient, dominant negative erbB-2 variant. 782 11

We have exploited the differences in binding affinities of the chicken epidermal growth factor (EGF) receptor for EGF and transforming growth factor alpha (TGF alpha) to study the role of the B-loop beta-sheet of these ligands in receptor recognition and activation. Although EGF and TGF alpha share similar secondary and tertiary structures imposed by three highly conserved intramolecular disulfide bonds, they have only 30-40% overall sequence identity. The B-loop beta-sheet is the major structural element in EGF and TGF alpha, but sequence similarity in this region is low. To investigate its role in receptor binding, we constructed two chimeric growth factors (mEGF/hTGF alpha 21-30 and mEGF/hTGF alpha 21-32) composed of the murine EGF (mEGF) amino acid sequence with residues 21-30 of the B-loop beta-sheet replaced by the equivalent residues of human TGF alpha (hTGF alpha); in chimera mEGF/hTGF alpha 21-32, asparagine 32, which lies at the boundary of the amino and carboxyl domains of mEGF, was also replaced by its hTGF alpha counterpart (valine). In initial studies using unpurified medium, it was found that the recombinant growth factors exhibited differing mitogenic potencies (mEGF/hTGF alpha 21-32 > mEGF/hTGF alpha 21-30 > mEGF) when assayed on chicken fibroblasts, even though they were equivalent in mitogenesis assays using cells expressing the human EGF receptor. After purification, mEGF/hTGF alpha 21-32 was found to be 50 times more potent than mEGF in the chick fibroblast mitogenesis assay and exhibited a 10-fold increase in relative affinity for the chicken EGF receptor; both growth factors still exhibited equivalent mitogenic and receptor binding activity when tested on cells expressing human EGF receptors. We conclude that the B-loop beta-sheet of hTGF alpha is an important determinant of EGF receptor binding affinity and biological activity.
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PMID:Contribution of the transforming growth factor alpha B-loop beta-sheet to binding and activation of the epidermal growth factor receptor. 782 92

The mutational activation of the neu proto-oncogene was analyzed in schwannomas of the peripheral nervous system transplacentally induced by N-ethyl-N-nitrosourea (ENU) in rats. All nine primary schwannomas investigated contained a T-->A transversion mutation at nucleotide 2012 of the neu gene, leading to the substitution of valine to glutamic acid in the transmembrane domain. Loss of the wild-type allele occurred in five of nine (56%) primary schwannomas. All four ENU-induced schwannomas transplanted in syngenic hosts (2-14 passages) showed the T-->A transversion mutation and loss of the wild-type allele. These data suggest that mutation of one allele together with loss of the wild-type allele constitutes two critical steps in the progression of rat schwannomas. Since c-erbB-2, the human counterpart of the rat neu gene is frequently involved by amplification in the development of human gastric cancer [30], we screened 12 rat gastric carcinomas induced by N-methyl-N-nitrosourea (MNU) for mutations in the neu gene. However, none of these tumors contained mutations.
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PMID:neu mutations and loss of normal allele in schwannomas induced by N-ethyl-N-nitrosourea in rats. 833 Mar

The receptor tyrosine kinase encoded by the neu/erbB-2 proto-oncogene is constitutively activated by a single valine to glutamic acid substitution at position 664 in the predicted membrane-spanning sequence of the receptor. We have explored the structural changes involved in receptor activation with polarized FTIR and magic angle spinning NMR spectroscopy. The hydrophobic transmembrane sequence folds into a well-defined alpha-helical structure spanning the membrane bilayer. Measurements of the pKa and 13C chemical shift anisotropy of Glu 664 reveal that the side chain carboxyl group is protonated and strongly hydrogen bonded. These studies provide direct evidence for glutamate hydrogen-bonding interactions in the mechanism of receptor dimerization and activation.
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PMID:Strong hydrogen bonding interactions involving a buried glutamic acid in the transmembrane sequence of the neu/erbB-2 receptor. 860 27

Certain specific point mutations within the transmembrane domains of class I receptor tyrosine kinases are known to induce altered behavior in the host cell. An internally controlled pair of peptides containing the transmembrane portion of the human epidermal growth factor (EGF) receptor (ErbB-1) was examined in fluid, fully hydrated lipid bilayers by wide-line 2H-NMR for insight into the physical basis of this effect. One member of the pair encompassed the native transmembrane sequence from ErbB-1, while in the other the valine residue at position 627 was replaced by glutamic acid to mimic a substitution that produces a transformed phenotype in cells. Heteronuclear probes having a defined relationship to the peptide backbone were incorporated by deuteration of the methyl side chains of natural alanine residues. 2H-NMR spectra were recorded in the range 35 degrees C to 65 degrees C in membranes composed of 1-palmitoyl-2-oleoyl phosphatidylcholine. Narrowed spectral components arising from species rotating rapidly and symmetrically within the membrane persisted to very high temperature and appeared to represent monomeric peptide. Probes at positions 623 and 629 within the EGF receptor displayed changes in quadrupole splitting when Val(627) was replaced by Glu, while probes downstream at position 637 were relatively unaffected. The results demonstrate a measurable spatial reorientation in the region of the 5-amino acid motif (residues 624-628) often suggested to be involved in side-to-side interactions of the receptor transmembrane domain. Spectral changes induced by the Val-->Glu mutation in ErbB-1 were smaller than those induced by the analogous oncogenic mutation in the homologous human receptor, ErbB-2 (Sharpe, S., K. R. Barber, and C. W. M. Grant. 2000. Biochemistry. 39:6572-6580). Quadrupole splittings at probe sites examined were only modestly sensitive to temperature, suggesting that each transmembrane peptide behaved as a motionally ordered unit possessing considerable conformational stability.
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PMID:Structural implications of a Val-->Glu mutation in transmembrane peptides from the EGF receptor. 1172 Sep 88


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